The present invention relates generally to cyclization of peptides. More particularly, the present invention relates to methods for treating peptides containing an even number of cysteine groups to produce a disulfide bond between pairs of such groups and to form a ring structure. The method of the invention is useful in the synthesis of peptides which have biological activity and which have therapeutic value in the treatment of certain diseases in animals and man.
Many peptides which contain a disulfide ring are known which are biologically active and are useful in the treatment of diseases. Somatostatin, which is described in U.S. Pat. No. 3,904,594 to Guillemin et al, has been shown to be effective in the inhibition of growth hormone by the pituitary gland. Somatostatin has been proposed for use in the treatment of acromegaly and diabetes. Somatostatin contains a disulfide bond between the cysteine residues in positions 3 and 14 in its amino acid sequence. Vasopressin and its analog lypressin are used as antidiuretic drugs in man. These peptides contain a disulfide bridge structure between cysteine groups at positions 1 and 6 in their amino aicd sequences. Oxytocin is used for the induction or stimulation of labor in humans, in animals and also to control postpartum uterine bleeding. Oxytocin contains a disulfide bridge structure between the cysteine groups at positions 1 and 6 in its amino acid chain. Calcitonins contain a ring structure involving cysteine groups at the first and seventh positions in their amino acid chain. Calcitonins are useful in the treatment of Paget's disease.
The amino acid sequences of the above described biologically active peptides containing cysteine groups joined by a disulfide bond in a ring structure are set forth in Table 1, herein below:
TABLE 1 ______________________________________ Somatostatin: HAlaGly ##STR1## OH Vasopressin: ##STR2## Oxytocin: ##STR3## Human Calcitonin: ##STR4## GlyThrTyrThrGlnAspPheAsnLysPhe HisThrPheProGlnThrAlaIleGlyVal GlyAlaProNH.sub.2 Porcine Calcitonin: ##STR5## Ser AlaTyrTrpArgAsnLeuAsnAsnPhe HisArgPheSerGlyMetGlyPheGlyPro GluThrProNH.sub.2 Bovine Calcitonin: ##STR6## SerAlaTyrTrpLysAspLeuAsnAsnTyr HisArgPheSerGlyMetGlyPheGlyPro GluThrProNH.sub.2 Salmon Calcitonin: ##STR7## ##STR8## ##STR9## ##STR10## ______________________________________
Eel calcitonin has the structure of salmon calcitonin except for having Asp in position 26, Val in position 27, and Ala in position 29.
The present invention is also applicable to the numerous calcitonin analogs known in the art, in which one or more of the amino acids of the naturally occurring sequence are modified or deleted, or one or more acids are added, with the retention or even enhancement of biological activity.
In U.S. Pat. Nos. 3,926,938, 4,062,815, 3,929,758, 4,033,940, 4,336,187, 4,388,235 and 4,391,747 are disclosed improved syntheses of calcitonins including the salmon calcitonin referred to above.